Jan-Inge Henter

Why rare diseases are an important medical and social issue.

Rare diseases aff ect a limited number of individuals (defi ned as no more than one in 2000 individuals in the European Union and no more than about one in 1250 in the USA), but the number of disorders that fi t this defi nition is very large (>5000 according to WHO). Therefore, the number of patients aff ected by a rare disease could be about 30 million in Europe and 25 million in North America. The true burden of rare diseases in Europe and elsewhere is diffi cult to estimate, since epidemiological data for most of these diseases are not available. Rare diseases are an important public-health issue and a challenge for the medical community. They are called health orphans, because rare diseases were neglected for many years. Similarly, before the USA passed the Orphan Drug Act in 1983, the pharmaceutical industry had neglected the development of treatments for rare diseases, hence the name orphan drugs. Public awareness about the diffi culties of patients with rare diseases was fi rst raised by the report of the National Commission on Orphan Disease of the US Government in 1989. The Commission’s hearings with hundreds of stakeholders highlighted issues that aff ected patients’ care, such as little information on rare diseases, diffi culties of fi nancing research, drawbacks of providing adequate health insurance and coverage of medical expenses, and the limited availability of eff ective treatments. The International Classifi cation of Diseases (ICD) that is used in most countries is not convenient for rare diseases. The absence of a universally recognised coding system is an obstacle for reliable registration of patients in national or international databases, preventing assessment of the economic and social eff ects of rare diseases. For some disorders, national or international registries are available, which have been set up and maintained by researchers, patients’ associations, public institutions, or drug companies. The European Rare Disease Task Force of the Health and Consumers Protection Directorate General of the European Commission has set up a working group to collaborate with WHO on ICD-10, and is considering all other existing classifi cations to provide the rare-diseases community with a uniform system. Assessment of the prevalence of rare diseases was attempted by the European Organization for Rare Diseases (Eurordis), and Orphanet, with the support of the European Commission. This study not only provided an estimate of the prevalence of several rare diseases (table), but also showed the absence of reliable data, low consistency between sources of information, and poor methodological quality of epidemiological studies. Additionally, facilities for biochemical or genetic testing are scarce. We use the collective term of rare diseases to include a very heterogeneous group of disorders that can aff ect any system. Most rare diseases are genetic disorders, which are often severely disabling, substantially aff ect life expectancy, and impair physical and mental abilities. These disabilities result in reduced quality of life, and aff ect an individual’s potential for education and earning capabilities. One example is inborn errors of metabolism, most of which are rare (prevalence between 1 in 1400 and 1 in 5000 livebirths). An Italian prospective study (1985–97) on patients aged 0–17 years revealed that, of the 1935 newborn babies with inborn errors of metabolism identifi ed by the study, only 11% reached adulthood. Rare diseases also pose a considerable burden on the aff ected families. This burden was assessed by sending a questionnaire to 2500 patients with chronic diseases (8·2% of which were rare diseases). Patients with rare disorders had the worst exper ience in terms of loss of social and economic oppor tunities, and of medical care. Patients with rare diseases face diagnostic delays. This issue was shown in a survey of eight rare diseases (Crohn’s disease, cystic fi brosis, Duchenne muscular dystrophy, Ehlers-Danlos syndrome, Marfan’s syndrome, Prader-Willi syndrome, tuberous sclerosis, and Lancet 2008; 371: 2039–41

Familial hemophagocytic lymphohistiocytosis and viral infections

A retrospective study was performed in 32 children with hemophagocytic lymphohistiocytosis, 16 of whom had affected siblings. Altogether 22 of these children, of whom the majority (13/22) were familial cases, had clinical or laboratory signs of infection. Laboratory analysis demonstrated Epstein‐Barr virus in five children, cytomegalovirus in three and human parvovirus in two. Two siblings with onset of familial hemophagocytic lymphohistiocytosis within one month of each other, both of whom demonstrated serological indications of a recent human parvoviral infection at onset, are described. It is concluded that a viral infection cannot serve as the sole criterion for distinguishing a virus‐associated hemophagocytic syndrome as an entity separate from familial hemophagocytic lymphohistiocytosis. Instead, it is suggested that viral infections may elicit a bout of the familial hemophagocytic lymphohistiocytosis disorder in genetically predisposed individuals.

Childhood idiopathic thrombocytopenic purpura in the Nordic countries: Epidemiology and predictors of chronic disease

Aim: To describe the epidemiology of idiopathic thrombocytopenic purpura (ITP) in the Nordic countries, to define clinical subgroups and to investigate factors predicting chronic disease. Methods: A prospective registration was done from 1998 to 2000, including all children with newly diagnosed ITP aged 0–14 y and at least one platelet count <30×109/l. Results: 506 children were registered and 423 followed for 6 mo. The incidence was 4.8/105 per year. Most children were aged 0–7 y (78%), with a predominance of boys, while patients aged 8–14 y had equal representation of the two sexes. There were seasonal variations determined by variations in postinfectious cases with sudden onset. The platelet count was <10×109/l in 58%, but bleeding manifestations were mild or moderate in 97%. The insidious form (symptoms for more than 2 wk) was more frequent in older children and girls, showed little seasonal variation, had milder manifestations and ran a chronic course in more than half the cases. Intracranial haemorrhages did not occur in the first 6 mo after diagnosis. Chronic ITP developed in 25%. The strongest predictor of chronic disease was insidious onset of symptoms (OR 5.97).

Parents' intellectual and emotional awareness of their child's impending death to cancer: a population-based long-term follow-up study

BACKGROUNDnWe aimed to study care-related determinants of when parents gain awareness of their childs impending death to cancer, and whether the duration of this awareness affects the parents long-term morbidity.nnnMETHODSnBetween August 2001 and October 2001, 449 of 561 (80%) parents who had lost a child due to any malignancy in Sweden between Jan 1, 1992, and Dec 31, 1997 (identified on the Swedish Causes of Death Register), answered a 365-item postal questionnaire designed to ascertain when, before the childs actual death, they had become intellectually and emotionally aware of the childs impending death (awareness time). The primary endpoints were intellectual awareness time (defined as time between intellectual realisation that a disease is fatal and the actual time of death) and emotional awareness time (defined as time between emotional realisation that a disease is fatal and the actual time of death). Parents awareness of less than 24 h was referred to as a short awareness time.nnnFINDINGSn436 parents answered the question about intellectual awareness and 433 parents answered the question about emotional awareness. 112 parents (26%) reported a short intellectual awareness time and 195 parents (45%) reported a short emotional awareness time. The risk of having short intellectual awareness time was increased if parents had absence of information on their childs fatal condition (mothers relative risk [RR] 3.6 [95% CI 2.3-5.5]; fathers 2.9 [1.8-4.5]) and if curative treatment was used towards the end of life (mothers 4.1 [2.6-6.5]; fathers 2.7 [1.7-4.2]). The risk of short emotional awareness time was increased if parents had absence of information indicating the child would die (mothers 1.5 [1.1-2.0]; fathers 1.8 [1.3-2.5]) and absence of talks about death with the other parent (mothers 1.5 [1.1-2.0]; fathers 1.7 [1.2-2.2]). Compared with fathers who had longer emotional awareness time, fathers with short emotional awareness time had an increased risk of depression (adjusted RR 1.8 [1.0-3.3]) and absence from employment due to sick leave or early retirement (RR 8.5 [1.1-67.8]) at follow-up. This difference was not noted for mothers.nnnINTERPRETATIONnHealth-care professionals can influence parents intellectual and emotional awareness of a childs impending death due to cancer. Short emotional awareness increases the risk of long-term depression in bereaved fathers.

Cerebromeningeal haemophagocytic lymphohistiocytosis

We describe 3 children with a progressive encephalopathy that was characterised by irritability, convulsions, cranial nerve palsies, ataxia, nystagmus, walking difficulties, delayed psychomotor development, hemiplegia/tetraplegia, visual disturbance, vomiting, neck stiffness, and non-specific signs of raised intracranial pressure. A final diagnosis was made in all 3 patients from necropsy material. The clinical features were ascribed to multiple inflammatory, predominantly lymphocytic, reactions and raised intracranial pressure. This condition is an atypical form of haemophagocytic lymphohistiocytosis, which normally presents with fever, hepatosplenomegaly, and cytopenias. By contrast, the disease pattern in our 3 children was dominated by cerebromeningeal involvement, which can precede the typical systemic symptoms of haemophagocytic lymphohistiocytosis. An awareness of this condition is important because treatments are available.

Long-term follow-up of Langerhans cell histiocytosis: 39 years' experience at a single centre.

AIMnTo evaluate the long-term outcome of Langerhans cell histiocytosis (LCH) in children.nnnMETHODSnWe re-evaluated all children (<15 y old at diagnosis) treated at our unit in 1962-1989. Histopathology specimens were reviewed and verified for 49 patients. Forty patients underwent physical examination and laboratory tests, and 38 were subjected to imaging, at a median time of 16 y (range 5.5-33.5) after diagnosis.nnnRESULTSnAltogether, 5/49 (10%) children died, all with multi-system disease and age <2 y at diagnosis. Age at diagnosis (p=0.001) and survival (p=0.014) for the 22 children with multi-system disease was significantly lower compared with the 27 children with single-system disease. The term maximal extent of disease was introduced since reactivation of LCH often tends to involve additional organs not previously affected by the disease. At follow-up, late sequelae had developed in 17/40 (42%) patients, including diabetes insipidus in 6/40 (15%), CNS complications in at least 4/40 (10%) (3/16, 19%, of multi-system patients) and late-stage pulmonary disease in 4/38 (11%). Seven out of 21 (33%) of the patients with multi-system disease were alive and healthy without sequelae at follow-up, as compared to 16/24 (67%) of those with single-system disease (p=0.026). Of 14 individuals 25 y at follow-up, senior high school had been completed in 7/9 (78%) with single-system and 1/5 (20%) with multi-system disease (at maximal disease extent) (p=0.091).nnnCONCLUSIONnMulti-system LCH is associated not only with increased mortality but also pronounced propensity for severe late sequelae; 51% of the patients (multi-system=33%, single-system=67%) were alive without sequelae at follow-up. Among multi-system patients, at least 19% suffered CNS sequelae.

Induction of apoptosis and caspase activation in cells obtained from familial haemophagocytic lymphohistiocytosis patients

Familial haemophagocytic lymphohistiocytosis (FHL) is a rare and uniformly fatal disorder of early childhood characterized by fever, hepatosplenomegaly, cytopenia and widespread infiltration of vital organs by activated lymphocytes and macrophages. In order to test whether the massive accumulation of immune cells in these patients is associated with a perturbation of apoptosis, lymphocytes were isolated from eight patients and subjected to the chemotherapeutic agent etoposide or agonistic anti‐Fas monoclonal antibodies in vitro. These stimuli elicited a normal apoptotic response in FHL patient cells when compared to healthy controls, as determined by phosphatidylserine exposure, DNA fragmentation, in vitro cleavage of the caspase‐3‐like substrate aspartate‐glutamate‐valine‐aspartate‐7‐amino‐4‐methyl‐coumarin (DEVD‐AMC) and proteolysis of the anti‐apoptotic protein Bcl‐2. In addition, the degree of constitutive and Fas‐triggered apoptosis in freshly isolated neutrophils was monitored in three children, with similar results. These studies indicate that immune cells derived from FHL patients are not inherently resistant to apoptosis induction. Specifically, etoposide‐induced and Fas‐triggered activation of intracellular caspases appears to remain intact in these individuals. However, the degree of spontaneous activation of caspase‐3‐like enzymes in activated lymphocytes was attenuated in three of the four patients tested prior to initiation of therapy, suggesting a possible biological deficiency in these individuals.

Familial Hemophagocytic Lymphohistiocytosis: Too Little Cell Death Can Seriously Damage Your Health

Familial hemophagocytic lymphohistiocytosis (FHL) is a rare and fatal disease of early childhood characterized by a non-malignant accumulation of activated T lymphocytes and histiocytes in the reticuloendothelial system. Moreover, immune system derangement, with prominent hypercytokinemia and low or absent cytotoxic T and natural killer (NK) cell activity, is a consistent feature of this autosomal recessive disorder. Recent work has demonstrated that the degree of spontaneous caspase activation in FHL lymphocytes is attenuated in vitro whereas Fas-mediated caspase activation and apoptosis induction remains unmitigated, and FHL can thus be distinguished from the related chronic disorder of immune regulation termed autoimmune lymphoproliferative syndrome or ALPS. However, subsequent studies have identified mutations in the gene encoding perforin, a cytotoxic granule constituent required for apoptotic killing of target cells, in a number of FHL patients. Hence, the underlying defect in FHL may be conceived of as a lack of apoptosis triggering within the immune system, rather than apoptosis resistance per se. These observations represent an important step in our understanding of the pathogenesis of FHL and also serve to emphasize the pivotal role of cellular (perforin-based) cytotoxicity in the regulation of immune homeostasis.

Myelodysplastic syndrome following epipodophyllotoxin therapy in familial hemophagocytic lymphohistiocytosis.

The prognosis for patients with familial hemophagocytic lymphohistiocytosis (FHL) is poor, but the survival of affected children has been markedly prolonged by treatment with the epipodophyllotoxin derivatives etoposide and teniposide and by bone marrow transplantation. Secondary malignancies following epipodophyllotoxin therapy, including myelodysplastic syndrome (MDS) and acute myelocytic leukemia (AML), have recently been reported. We describe a 9-year-old boy, treated with epipodophyllotoxins for FHL since he was 3 years old, who developed MDS. He was administered etoposide (cumulative doses of 6.9 g/m2 intravenously and 13.6 g/m2 orally) and teniposide (3.4 g/m2 intravenously), but no other systemic antineoplastic drugs. This is, to our knowledge, the first report of a child with FHL developing MDS or AML. Moreover, MDS or AML following administration of epipodophyllotoxins as the sole systemic chemotherapeutic drug has not been reported previously. Supportive treatments, including the use of immunomodulating drugs, may reduce the risk for secondary leukemia in patients with FHL.

Longitudinal Analysis of Infantile Growth in Children with Celiac Disease

ABSTRACT. The aim of the present study was to describe linear growth of infants with celiac disease, using the “ICP‐growth model”. Supine length during the first three years of life was studied longitudinally in 63 infants with diagnosed celiac disease. “Undisturbed” linear growth was seen during the first six postnatal months followed by reduced growth during the second half of the first year. After 1.5 years of age a pattern of catch‐up growth was observed, leading to an average attained length at 3 years of age similar to that of the controls. According to the “ICP‐growth model”, normal linear growth can mathematically be represented during the first 3 years of life by an Infancy component with the addition of a Childhood component, the latter acting from the second half of the first postnatal year. The onset of the Childhood component (assumed to represent the age at which growth hormone begins to influence linear growth significantly) was delayed by about an average of 3 months, which is in agreement with the observed reduction in gain during the second half of the first year of life. Children suffering from celiac disease and with “late” onset of the Childhood component were shorter at 1, 2 and 3 years of age than those with “normal” onset. The results of this investigation show that ICP‐based growth charts are helpful in detecting and monitoring growth for children with celiac disease, and indicate a possible mechanism whereby malabsorption (and perhaps secondary malnutrition) leads to reduced growth velocity.